Functionalized Cyclotriproline - A Bowl-Shaped Tripodal Scaffold

Abstract

The synthesis and conformational analysis of C₃-symmetric cyclotri[(4S)-aminoproline] as a bowl-shaped scaffold for three-armed receptors is described.

Key words

cyclic peptides - scaffolds - proline - cyclization - receptors

References

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7

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate; TBTU: N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium-tetrafluoroborate; PyBop: benzotriazole-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate.

10

Preparation of 1a: The HCl salt 5a (440 mg, 0.94 mmol) was dissolved in anhyd DMF (17 mL) and added within 1 h via syringe pump to a stirred solution of HATU (1.07 g, 2.81 mmol) and Hünig’s base (1.44 mL, 8.43 mmol) in anhyd DMF (90 mL). The reaction mixture was stirred for an additional hour before removal of all volatiles at reduced pressure. The remaining oil was extracted with CH₂Cl₂ (100 mL) and 2 M HCl (50 mL). The aqueous layers were extracted with CH₂Cl₂ (2 × 50 mL), the organic layers were washed with brine and dried over Na₂SO₄. Filtration and evaporation of the solvent at reduced pressure followed by flash chromatography on silica gel (EtOAc) yielded the cyclotripeptide 1a (285 mg, 0.69 mmol, 73%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 5.07 (dd, J = 8.1 Hz, 2.1 Hz, 3 H; Hα), 4.52 (dd, J = 12.5 Hz, 8.1 Hz, 3 H; Hδ), 4.04 (dtd, J = 9.9 Hz, 8.1 Hz, 5.3 Hz, 3 H; Hγ), 3.14 (dd, J = 12.5 Hz, 8.2 Hz, 3 H; Hδ), 2.64 (ddd, J = 13.9 Hz, 5.2 Hz, 2.1 Hz, 3 H; Hβ), 2.54 (ddd, J = 13.8 Hz, 10.0 Hz, 8.2 Hz, 3 H; Hβ). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 165.9, 56.3, 55.7, 49.3, 34.1. FT-IR (NaCl): 2108, 1646, 1441, 1362, 1263, 1211 cm^-1. ESI-MS: m/z Calcd for C₁₅H₁₈N₁₂O₃ [M + Na]⁺ 437. Found: 437 (100%). Elemental analysis calcd for C₁₅H₁₈N₁₂O₃ (414.16): C, 43.48; H, 4.38; N, 40.56. Found: C, 43.41; H, 4.34; N, 40.50.

11

Performing the cyclization at higher or lower dilution did not improve the yield any further.

17

The distance of 7-8 Å has proven to be an ideal distance between the attachment sites of the recognition elements of two-armed receptors, see ref 3.